Analytica Chimica Acta 546 (2005) 174181

Simultaneous determination of 17 sulfonamide residues in porcine meat,

kidney and liver by solid-phase extraction and liquid
chromatographytandem mass spectrometry
Bing Shao
a,
, Dan Dong
a,d
, Yongning Wu
b
, Jianying Hu
c
, Juan Meng
a
,
Xiaoming Tu
a
, Shukun Xu
d
a
Institute of Nutrition and Food Hygiene, Beijing Center for Disease Prevention and Control, Beijing 100013, China
b
National Institute of Nutrition and Food Safety, Chinese Center for Disease Prevention and Control, Beijing 100050, China
c
College of Environmental Sciences, Peking University, Beijing 100085, China
d
Department of Applied Chemistry, Northeastern University, Shenyang 110004, China
Received 14 January 2005; received in revised form 29 April 2005; accepted 3 May 2005
Available online 20 June 2005
Abstract
A precise and reliable method, using normal phase cartridge clean-up and liquid chromatography coupled with tandem mass spectrometry
has been developed for measuring the residues of 17 sulfonamides in porcine tissues included in meat, liver and kidney. The parameters of
mass spectrometer were optimized by continuous direct injection through a syringe pump. The composition and additives for mobile phases
were also evaluated and the optimum one was methanolwater containing 0.1% formic acid. A liquidliquid extraction and Sep-Pak silica
clean-up procedure was developed for sample preparation. The method was validated and found to be satisfactorily linear, selective and robust.
Recoveries ranged from 52 to 120% for all compounds at three different spiking levels and the limit of detections (LODs) ranged from 0.01
to 1.0 ng/g depending on various compounds.
2005 Elsevier B.V. All rights reserved.
Keywords: Sulfonamides; LCMS/MS; Porcine tissues
1. Introduction
Sulfonamides (Fig. 1) are a group of synthetic antibiotics
that have played an important role as effective chemother-
apeutics in bacterial and protozoan infections in veterinary
medicine practice. They have been widely used in animal feed
as growth promoters to prevent and treat a series of diseases in
animals feeding, such as infectious diseases of digestive and
respiratory tracts. As a consequence of their extensive usage,
considerable attention has been paid to the potential human
health risk due to their carcinogenic potency and possible
antibiotic resistance [14]. To safeguard human health, the

Corresponding author. Tel.: +86 10 64212461x503;

fax: +86 10 64214405.
E-mail address: shaob@bjcdc.org (B. Shao).
European Union (EU) and other countries including China
have established safe maximum residue limits (MRLs) at the
total level of 100 g/kg in food of animal origin [5,6].
Pork is the main kind of meat consumed in China because
of its high nutrition, inexpensiveness and availability. It is
estimated that the average consumption in 2005 will be
54.4 kg/person/year [7], and pork will be the main contributor
for exposure to sulfonamides if not well controlled. There-
fore, it is necessary to develop a sensitive and reliable method
to monitor the sulfonamide residue level in tissues. Many
methods such as GCMS, GC, LC and LCMS have been
developed to analyze sulfonamide residue in food. GC [8]
and LC[911] lack sensitivity and specicity and can only be
used for screening of high levels of residues. GCMS [12,13]
methods require derivation because of the high polarity and
low volatility of sulfonamides.
0003-2670/$ see front matter 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.aca.2005.05.007
B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181 175
Fig. 1. Sulfonamides structure, name, CAS number and pK
a
1
value.
Liquid chromatography coupled with electrospray ion-
ization mass spectrometry (LCESI-MS) has proven to be
a promising technique for residual analysis with its high
selectivity, specicity and sensitivity for the high polarity
of sulfonamides [1323]. At present, only ve LCESI-MS
methods have been reported to detect the residues of sulfon-
amides in meat [14,16,19,21,23]. However, when using the
highly sensitive and specic LCMS, the sample purication
was ignored, which led to high limits of detection (LODs),
over 1 g/kg. This value was also obtained using LC with
uorescence detection [24].
A clean sample is an important factor closely associated
with the sensitivity of an analytical method. The preva-
lent clean-up procedures are liquidliquid extraction (LLE)
using hexane to remove fat [14,27] and reversed phase solid-
phase extraction (SPE) used to concentrate the samples
[9,17,18,26]. Fuh [25] used neutral Alumina and macrop-
orous copolymer SPE column for clean-up as well as capil-
lary electrophoresis to detect eight sulfonamides in meat and
determined the LODcompared with that using LCMS. Hela
and Tarbin [13,18] used ion-exchange SPE to purify sample
extracts of egg and animal tissues. However, the fat in tissues
176 B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181
is mainly responsible for interference. After liquidliquid
extraction and solid-phase extraction (SPE) using reversed
phase and ion-exchange sorbents, only part of the fat is
removed.
To overcome these problems, in this study, a silica nor-
mal phase SPE method combined with LCESI-MS/MS was
applied to detect the wide range polarity of 17 sulfonamides
in pork, and porcine liver and kidney. Comprehensive sam-
ple preparation and mobile phase composition and additives
optimization procedures with good resolution and high sen-
sitivity are descried.
2. Experimental
2.1. Standards and reagents
Organic solvents such as methanol, acetonitrile, hex-
ane, chloroform and 1-propanol were all pesticide residue
grade, commercially available from Scharlau Chemic S.A.
(Barcelona, Spain). Formic acid (99%), acetic acid (99%)
and triuoroacetic acid (99%) were from Acros Organics
(New Jersey, USA). Anhydrous sodium sulfate and ammo-
niumformate were all analytical grade (Beijing, China). Ultra
pure water was made by the Milli-Q ultrapure system (Mil-
lipore, Bedford, MA, USA). Sulfonamide standards were
obtained from Sigma (St Louis, MO, USA). Drug names,
structures and pK
a
are shown in Fig. 1. Internal standard,
13
C
6
-sulfamethazine (
13
C
6
-SMA, 90%) was obtained from
Cambridge Isotope Laboratories (50 Frontage Road, MA,
USA). All standards were stored at 20

C. Sep-Pak silica,
amino-propyl and cyan-propyl solid-phase extraction car-
tridges containing 500 mg materials (3 ml) were purchased
from Waters (Milford, MA, USA). To avoid cross contami-
nation, all the glassware was heated for 4 h at 400

C prior to
use. In addition, procedural blanks were conducted for each
batch of samples to ensure minimal contamination.
Stock solutions were prepared for all standard substances
at 1000 mg/l in acetonitrile. Spiking and calibration mixtures
at various concentration levels were obtained by combining
aliquots of stock solutions and internal standard with mobile
phase and storing at 4

C. The concentration of internal stan-

dard in all the calibration mixtures and nal sample solutions
was 50 g/l.
2.2. Sample preparation
Ten grams of minced porcine tissues was placed into a
50 ml polypropylene tube and spiked with 50 ng
13
C
6
-SMA.
Ten grams baked anhydrous sodium sulfate and 15 ml ace-
tonitrile was then added. The sample were homogenized with
a rener for about 1 min, and then centrifuged at 8000 rpm
for 10 min at 0

C. The supernatant was decanted into a sep-

aratory funnel. The residue was extracted two times with
15 ml acetonitrile. The extracts were combined. Then 20 ml
n-hexane was added into acetonitrile extracts, and each sam-
ple was mixed and separated. The upper layer was discarded
(n-hexane) and 5 ml 1-propanol was added. The solvent was
evaporated to near dryness by a rotary evaporator at 30

C.
The residue was dissolved by ultrasonication for 30 s with
0.4 ml chloroform and 3.6 ml n-hexane. The solution then
was passed through the Sep-Pak Silica solid-phase extrac-
tion cartridge preconditioned by 6 ml n-hexane without any
pressure. Five milliliters n-hexane was used to wash the inter-
ference. The analytes were eluted sequentially with 6 ml
methanolacetone (v/v, 1:1) and 6 ml acetone. The eluents
were dried under a gentle nitrogen stream, and reconstituted
with 1 ml mobile phase for LCMS/MS analysis.
2.3. LCMS/MS analysis
Identication and quantication of analytes were carried
out using an Alliance 2695 (Waters, USA) liquid chromatog-
raphy equipped with a Quattro Ultima Pt (Micromass, UK)
tandem mass spectrometer. The Xterra

MS C-8 column
(150 mm2.1 mm I.D., 3.5 m, Waters, USA) was used for
LC separation. The temperature of the column oven was
28

C, the ow rate was 0.2 ml/min, and the injection vol-

ume was 10 l. Methanol and water were used as mobile
phase containing 0.1% formic acid. The methanol was lin-
early increased from 3 to 15% in 13 min, then increased to
40%in 9 min and held for 3 min, it was then increased to 80%
in 5min, then increased to 100% in 1 min and held for 5 min,
and nally it was brought back to 3% and held for 20 min
until the next injection.
The mass spectrometer was operated in electrospray pos-
itive ion mode. The capillary voltage was held at 3.5 kV. The
cone voltage was 78 V. The multiplier voltage was 650 V.
The nebulizing, desolvation and cone gas were supplied with
UHP nitrogen. The nebulizing gas was adjusted to the max-
imum, and the ow of desolvation gas and cone gas were
set to 450 and 0 l/h, respectively. The source temperature and
desolvation gas temperature were held at 100 and 300

C
respectively. The radio frenquency (RF) lens 1 and RF lens
2 were set as 40 and 0.5 V. The ion energy 1 and ion energy
1 were both 0.5 V. The entrance and exit voltage were zero.
The collision gradient was 1.9. During tandem mass spec-
trometric analysis, UHP argon was used as collision gas and
the pressure of collision chamber was held 3.1 10
3
mbar.
The multiple reaction monitoring transition conditions used
for quantitation of various sulfonamides are listed in Table 1.
3. Results and discussion
3.1. Optimizing LCMS/MS condition
To achieve the maximum sensitivity, the mass spectrome-
try parameters including ionization mode, the capillary volt-
age, cone voltage, source temperature and desolvation gas
temperature, desolvation gas and cone gas ow, the pres-
sure of the collision chamber, and the collision energy were
B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181 177
Table 1
Sulfonamide data acquisition parameters (LCMS/MS) and instrumental detection limit
Chemicals Retention time (min) MH
+
(m/z) Daughter ion (m/z) Collision energy (eV) DL
a
(pg)
SA 3.49 173.2 156.0 132.0 9 0.7
SIM 12.23 279.3 124.1 186.1 156.0 18 0.2
SDZ 13.19 251.3 156.1 108.1 92.1 15 0.3
SPD 15.53 250.3 156.0 184.2 15 0.2
STZ 15.78 256.4 156.1 108.1 92.1 19 0.3
SMR 17.34 265.3 156.0 172.1 110.1 15 0.1
SDMD 20.74 279.2 186.0 124.1 156.0 20 0.5
SME 21.21 281.3 156.0 126.1 108.0 15 0.3
SMT 21.33 271.2 156.0 108.0 92.0 14 0.1
SMP 21.71 281.3 156.0 126.1 108.1 15 0.1
SCP 22.42 285.2 156.0 207.1 12 0.3
SMX 23.49 254.3 156.0 108.1 92.1 13 0.1
SIX 24.66 268.2 156.0 113.1 108.1 15 0.2
SMO 24.66 268.3 156.0 113.1 108.1 16 0.2
SDM 28.10 311.4 156.1 108.1 92.1 19 0.1
SQX 29.17 301.2 156.0 107.9 15 0.1
SNT 32.35 336.4 156.0 294.3 198.1 10 0.2
13
C
6
-STZ 20.67 284.5 185.8 123.9 161.2 19
a
DL: detection limit (three times of the signal-to-noise ratio).
rst optimized by direct ow infusion of each standard. The
results indicated that the positive mode was more favorable
than the negative ion mode. The characteristic ion and col-
lision energy for each compound are listed in Table 1. All
the compounds except isotopic internal standard gave a char-
acteristic ion at m/z 156.0, although the abundance may be
different depending on the variable compounds.
As for the sulfonamides with a wide pK
a
range investi-
gated in our study, the properties of mobile phases such as
pH and additives can affect the LC resolution. In addition,
considering the characteristics of electrospray ionization, the
mobile phase composition and additive may signicantly
affect the response. Therefore, the additive and the mobile
phase composition were comprehensively investigated. In
previous paper [22], the mobile phase parameter, concen-
tration of formic acid, pH of the aqueous solution and ratio
of the aqueous solution and the organic solvent were opti-
mized using methanolacetonitrile 0.05 M formic acid as
mobile phase only to achieve a satisfactory separation of
10 sulfanamides. For the mobile phase composition in this
study, the response using methanolwater as mobile phase
was signicantly higher than that using acetonitrilewater.
In addition, the organic phase content can signicantly affect
the sensitivity. Among the 17 sulfonamides, the sensitivity of
the sulfamilamide (SA) was far lower than others, as its elu-
tionat the time of 3.49 mincontainedabout 7%of methanol in
the mobile phase composition. However, if the mobile phase
composition started with a high content methanol, the SA
would elute at a dead volume without retention due to its
high polarity.
Among these additives such as formic acid, acetic acid,
triuoroacetic acid and ammonium acetate, different con-
centration levels were also optimized. Taking formic acid
as an example, the results suggest that the resolution and
sensitivity of the mixture standard increased with the increas-
ing of the formic acid concentration from 0.05% (pH=2.98)
to 0.1% (pH=2.28); however, the resolution and sensitivity
decreased when the formic acid concentration increased to
0.15%(pH=1.91). The change of resolution can be attributed
to the change of polarity for the sulfonamides with differ-
ent pK
a
, which induced to the change of the capacity fac-
tor of each sulfonamide. However, the concentration higher
than 0.1% may suppress the ionization. Acetic acid, triuo-
roacetic acid and ammonium acetate were also optimized as
above, 0.2% of acetic acid (pH=3.43), 0.1% triuoroacetic
acid (pH=2.28) and 5 mmol/l ammoniumacetate (pH=6.16)
were the optimal composition and additives. In comparison
with the response using formic acid, 0.1% formic acid was
the optimum additive.
3.2. Sample clean-up
In addition to the instrument parameters, mobile phase
composition and additives, the clean-up procedure is an
important factor that has an inuence on sensitivity. For
foods of animal origin, the fat is a critical factor, as it can
decrease the sensitivity and shorten the lifetime of a column.
Liquidliquidextractionusingn-hexane canonlyremove part
of the fat. Therefore, normal phase SPE procedures are often
used to purify the bio-samples and enhance the methods
sensitivity. However, only one method for sulfonamides has
reported the further clean up using normal phases SPE after
liquidliquid extraction from tissue [25]. The Sep-Pak silica,
amino-propyl and cyan-propyl SPE were used to purify the
crude sample extracts at 100 g/kg fortication to evaluate
efciency of clean up. The results (not listed in this paper)
indicated that the Sep-Pak silica was satisfactory using 6 ml
acetonemethanol (1:1) and 6 ml acetone as eluent.
178 B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181
Fig. 2. The chromatograms of spiking samples containing 10 g/kg of each compound.
B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181 179
Fig. 2. (Continued).
3.3. Method performance
The chromatograms of spiking samples containing
10 g/kg of each compound are shown in Fig. 2. Because of
their similar structures and the limited commercial availabil-
ity of stable isotope compounds, only one internal standard
was used. The calibration curves for detection of the analytes
were obtained by performing a linear regression analysis on
standard solution using the ratio of the standard area to inter-
nal standard area (each sulfonamide for
13
C
6
-SMA) against
the analytes concentration ranging from 1.0 to 200 g/l
containing 50 g/l internal standard, i.e. 10.02000 pg with
10 l injection. The linearity obtained for all analytes were
good with correlation coefcients higher than 0.999. The
instrumental detection limits (IDL) with 10 l injection
ranged from0.1 to 0.7 pg depending on different compounds,
Table 2
Recoveries, RSD and LOD of spiked porcine meat tissue
Compound Spiked level 1 g/kg Spiked level 5 g/kg Spiked level 10 g/kg LOD (ng/g)
Meat Liver Kidney Meat Liver Kidney Meat Liver Kidney Meat Liver Kidney
SA 65.2 (11.6) 69.6 (5.8) 74.3 (3.1) 75.8 (8.9) 72.8 (10.2) 82.3 (14.4) 90.9 (9.4) 74.5 (13.6) 68.8 (14.8) 0.3 0.5 0.4
SIM 69.8 (8.1) 66.2 (7.3) 58.1 (8.3) 67.8 (10.1) 64.4 (8.5) 60.4 (8.5) 69.0 (13.6) 72.7 (6.1) 68.5 (5.7) 0.02 0.02 0.04
SDZ 98.2 (11.5) 78.0 (6.4) 67.9 (5.0) 95.1 (10.7) 71.8 (9.8) 61.5 (5.7) 102.0 (8.9) 75.9 (8.9) 60.9 (9.9) 0.02 0.08 0.33
SPD 105.3 (4.7) 88.0 (3.6) 88.9 (2.7) 91.4 (7.6) 89.4 (4.2) 78.8 (10.8) 89.4 (13.1) 82.6 (8.9) 70.7 (7.0) 0.02 0.02 0.06
STZ 68.3 (14.0) 70.2 (10.9) 85.4 (7.1) 64.7 (2.7) 88.7 (14.5) 76.4 (10.5) 85.0 (19.8) 90.3 (15.3) 76.7 (8.1) 0.01 0.06 0.15
SMR 102.3 (11.3) 85.1 (9.1) 87.7 (10.4) 114.0 (6.7) 89.3 (7.1) 93.9 (5.1) 108.3 (5.6) 97.2 (8.8) 100.5 (8.8) 0.03 0.03 0.07
SDMD 112.1 (5.2) 105.4 (8.2) 114.9 (6.2) 108.0 (2.9) 111.7 (5.4) 112.3 (4.8) 111.0 (8.4) 119.2 (6.2) 114.1 (4.1) 0.05 0.04 0.14
SME 65.6 (7.2) 56.7 (13.0) 55.5 (4.6) 71.4 (11.3) 67.4 (8.2) 72.8 (9.4) 81.3 (17.4) 65.4 (11.0) 68.3 (5.4) 0.01 0.05 0.12
SMT 65.2 (5.2) 83.0 (10.5) 84.1 (14.7) 97.1 (6.7) 97.8 (7.4) 87.1 (9.8) 117.4 (3.5) 105.9 (10.8) 110.1 (7.9) 0.05 0.08 0.11
SMP 89.1 (6.8) 86.0 (5.5) 83.3 (2.9) 95.9 (6.6) 84.9 (9.1) 78.8 (4.2) 112.2 (2.9) 90.0 (5.4) 82.5 (8.6) 0.05 0.06 0.08
SCP 90.7 (14.3) 89.9 (10.9) 91.1 (13.0) 83.3 (10.3) 94.0 (12.9) 79.7 (6.3) 94.9 (10.8) 101.8 (7.2) 95.3 (11.6) 0.03 0.03 0.11
SMX 111.9 (14.4) 70.9 (5.5) 78.2 (6.6) 97.2 (5.1) 78.1 (8.4) 66.7 (16.3) 91.7 (10.8) 79.3 (9.6) 75.1 (5.7) 0.02 0.01 0.05
SIX 90.8 (8.4) 95.2 (9.7) 107.1 (12.0) 94.7 (6.0) 89.67 (6.7) 79.8 (12.1) 85.2 (10.4) 104.4 (8.1) 89.1 (12.1) 0.02 0.02 0.08
SMO 87.7 (13.3) 95.1 (14.2) 111.2 (8.6) 60.8 (14.2) 101.4 (9.6) 86.7 (11.8) 64.5 (9.7) 94.9 (16.4) 84.4 (10.9) 0.02 0.02 0.06
SDM 78.9 (18.6) 84.6 (15.9) 84.6 (14.3) 83.8 (8.5) 95.2 (16.4) 73.0 (14.8) 97.1 (13.5) 89.8 (14.2) 75.7 (9.5) 0.02 0.02 0.05
SQX 59.9 (7.0) 67.3 (6.5) 64.2 (15.5) 60.8 (4.1) 62.5 (9.0) 57.6 (8.8) 64.5 (4.4) 62.6 (8.5) 56.6 (9.6) 0.05 0.08 0.20
SNT 53.5 (7.1) 52.33 (12.3) 53.0 (16.2) 52.5 (6.2) 54.2 (14.1) 52.4 (15.8) 62.7 (14.8) 58.5 (14.5) 53.1 (8.9) 0.10 0.17 1.00
Values in parentheses are % relative standard deviations for n =5.
180 B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181
Fig. 3. The typical chromatogram of one sample available from local market.
respectively, which was estimated at a signal-to-noise (S/N)
ratio of 3. The recoveries of analytes in ve replicates at
each level were evaluated at three levels by spiking 10.0,
50.0 and 100.0 ng of each standard analyte to 10.0 g tissues.
The results are listed in Table 2. The average recoveries of
each compound are ranged from 52 to 120%. Generally, the
recoveries in kidney were higher than those in meat, followed
by those in liver. SDMDis widely used and could be found in
most of the sample; therefore, the recoveries were all higher
than 100 for all sample matrices. This may be the inuence
of the background sample, although the background value
has been subtracted. In addition, according to the suggestion
of AOAC on the analysis of residues [28], these values are
acceptable. The reproducibilities of this method represented
by the percent of the relative standard deviation (RSD) at
each fortication level are also summarized in Table 2 and
showed that the method precision was within 20%, which is
satisfactory. The within-day and between-day reproducibil-
ities were evaluated by injecting a standard mixture ve
times at three different levels each day for ve consecutives
days. The within-day reproducibilities ranged from 1.9 to
3.8% and between-day reproducibilities ranged from 3.5
to 8.2%. The limits of detection for sulfonamides in pork,
liver and kidney tissues, dened as the concentration which
yield an S/N equal to three, are described in Table 2. The
LODs for all the compounds were lower than 1 g/kg, which
was much higher than those reported in previous papers
[1323].
4. Analysis of real samples
This method has been used to analyze 15 porcine meat
samples available from local market. Among the 15 samples,
SMEwas found in 10 samples with concentration levels rang-
ing from 0.01 to 15.43 g/kg, and SDMD ranging from 0.08
to 7.34 g/kg in nine of the 15 samples. SDZ, SMXand SQX
were alsofoundonlyinone sample, witha concentrationlevel
lower than 0.4 g/kg. SAwas found in two of the 15 samples,
with a concentration 3.47 and 0.98 g/kg, respectively. Fig. 3
shows a typical chromatogram of one sample available from
the local market with SA (0.98 g/kg), SDMD (0.81 g/kg)
and SMT (0.03 g/kg) found in the sample.
5. Conclusions
In this study, a clean-up procedure and LCMS/MS
method has been developed and optimized to measure
the residues of 17 sulfonamides in porcine tissues. The
methanolwater containing0.1%formic acidas mobile phase
showed good LC resolution and MS sensitivity. The LODs
were 24 magnitudes lower than the MRLs of dened by EU.
B. Shao et al. / Analytica Chimica Acta 546 (2005) 174181 181
Acknowledgement
The authors wish to acknowledge the Beijing Natural
Science Foundation for nancial support under grant num-
ber 7041004 and the Ministry of Science and Technology
(2001BA804A18-02, 2001BA804A55).
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